This proposal is aimed at fully characterizing the extent to which retrograde transport and/or endocytosis are involved in a myogenic model of Spinal Bulbar Muscular Atrophy (SBMA). SBMA is a X-linked lower motoneuron disease characterized by adult onset muscle weakness, atrophy, and significant depletion of motneurons. It has been widely accepted that muscle weakness and atrophy result from loss of innervation from motoneurons. Our group has unexpectedly engineered a transgenic mouse model for SBMA which shows disease symptoms in androgen-dependent fashion by selectively over-expressing the wild-type AR gene exclusively in muscle tissue, challenging two tenets of the current dogma about this disease: 1) that SBMA originates in motoneurons, and 2) that an expansion of CAG repeats exceeding 40 within the AR protein is required to trigger SBMA. Our model of SBMA shows many of the hallmark pathological features of this disease, including androgen-dependent loss of motor function accompanied by marked muscle atrophy and motoneuron death. Most recently we have discovered that our transgenic mice showing SBMA disease symptoms also show marked deficits in retrograde labeling of motoneurons using cholera toxin horseradish peroxidase (CT-HRP). The experiments proposed within this fellowship are designed with the intent of identifying the extent to which a deficit in retrograde transport is responsible for the pathogenesis in our muscle model of SBMA. We have designed ours experiments to evaluate the extent to which potential changes in axonal transport and synaptic morphology correlate with changes in motor function. This information should tell us whether changes in retrograde transport represent a potential cause or is simply a byproduct of the disease, these results will be important for guiding future hypotheses regarding the disease. Our model, which over-expresses wt AR protein only in skeletal muscle fibers provides an unique method to investigate the contribution of muscle to the SBMA phenotype. Hence, we have also proposed to investigate the usefulness of known SBMA therapeutics on our muscle model of SBMA. Successful therapeutic intervention for our model of SBMA would provide compelling evidence that targeting skeletal muscle fibers is likely to yield effective therapeutic agents to treat SBMA. This proposal carries profound implications for other polyglutamine and neuromuscluar diseases in that it suggests a muscular component to these diseases. Such implications ask, are these diseases more muscular or neurological in origin? Answering such questions could have profound impact on how neuromuscular disease should be treated in the future.